Project Summary The Psychiatric Genomics Consortium (http://pgc.unc.edu), now in its eighth year, is one of the most innovative experiments in the history of psychiatry. We have unified much of the field to enable rapid progress in elucidating the genetic basis of psychiatric disorders. We have 800+ investigators from 36 countries and >400K subjects. The PGC has attracted a cadre of outstanding scientists whose careers center on our work. The PGC has published 17 main papers plus 31 secondary analysis/methods development papers. The most important was the landmark Nature paper identifying 108 loci for schizophrenia (SCZ). Due to our open-source approach, there are 75+ papers that use PGC results, and we know of numerous groups that are using our findings to direct basic and applied research (including therapeutic development). More work is needed. Large amounts of new data will be available to the PGC in the next five years (largely without NIMH funding). We have developed a rigorous set of approaches that are yielding discoveries for all of the initial five disorders (which led to adding four new disorders). We thus have the unique opportunity to rapidly and efficiently increase our knowledge of common and rare variation in order to understand the causes and comorbidities of major psychiatric disorders. Our overarching goal is to identify ?actionable? variation via the empirical evaluation of the etiological, clinical, nosological, therapeutic, and biological significance of our genomic findings. We will continue the highly successful work of the PGC in understanding the roles of common genetic variation by: (a) comprehensively analyzing historically large GWA samples for nine major psychiatric disorders; (b) evaluating how genetic risk scores impact development and clinical symptom patterns; (c) understand the genetic relationship among psychiatric disorders and across psychiatric disorders and many other CNS diseases. We will enhance our work on the discovery of rare variation by: (d) conducting mega-analyses of copy number variation across nine psychiatric disorders; (e) efficiently and inexpensively re-sequencing regions implicated by GWAS (200 candidate genes in 20,000 subjects); and (f) using the hundreds of clinicians in the PGC, identify rare densely affected pedigrees to enable searches for rare variants of strong effect. Successful completion of this body of work will advance knowledge of the genetic basis of multiple psychiatric disorders. Our goal is to deliver ?actionable? findings, genomic results that (a) reveal the fundamental biology, (b) inform clinical practice, and (c) deliver new therapeutic targets. This is the central idea of the PGC: to convert the family history risk factor into biologically, clinically, and therapeutically meaningful insights. We have leveraged external funding from multiple sources to minimize NIMH budgetary requests.